CN104262346B - A kind of preparation method of bromfenac sodium dimer impurity - Google Patents
A kind of preparation method of bromfenac sodium dimer impurity Download PDFInfo
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- CN104262346B CN104262346B CN201410476547.9A CN201410476547A CN104262346B CN 104262346 B CN104262346 B CN 104262346B CN 201410476547 A CN201410476547 A CN 201410476547A CN 104262346 B CN104262346 B CN 104262346B
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- GMDBNSJLGOGUCW-YUMHPJSZSA-N CN(C(Cc1cc(C(c(cc2)ccc2Br)O)ccc1)=O)/C(/C(CC=C)C(c(cc1)ccc1Br)=O)=C\CC(N)=O Chemical compound CN(C(Cc1cc(C(c(cc2)ccc2Br)O)ccc1)=O)/C(/C(CC=C)C(c(cc1)ccc1Br)=O)=C\CC(N)=O GMDBNSJLGOGUCW-YUMHPJSZSA-N 0.000 description 1
- 0 CN(c1c(Cc2c3c(cccc4C(c5ccc(*)cc5)=O)c4[n]2)cccc1C(c1ccc(C=C)cc1)=O)C3=O Chemical compound CN(c1c(Cc2c3c(cccc4C(c5ccc(*)cc5)=O)c4[n]2)cccc1C(c1ccc(C=C)cc1)=O)C3=O 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention belongs to pharmaceutical technology field; the preparation method providing a kind of bromfenac sodium dimer impurity; including by 7-(4-benzoyl bromide)-1; the hydrolysis of 3-dihydro-indol-2-one obtains bromfenac; bromfenac is added in alkali hydroxide soln; crystallize obtains bromfenac sodium dimer impurity crude product, is added in ethyl acetate by bromfenac sodium dimer impurity crude product, obtains bromfenac sodium dimer impurity. Impurity in bromfenac sodium dimer impurity crude product is become to salt out by the present invention, achieves the polishing purification of bromfenac sodium dimer impurity simply, efficiently, and purity brings up to more than 99%, and preparation method is easy, and environmental benefit is good, and yield is high.
Description
Technical field
The invention belongs to pharmaceutical technology field, the preparation method being specifically related to a kind of bromfenac sodium dimer impurity.
Background technology
Bromfenac sodium is one of 2-amino-3-benzoylphenylacetic acids analog derivative; chemical name is 2-amino-3-(4-benzoyl bromide) sodium phenylacetate; structure is similar with ketoprofen and diclofenac; the synthesis of the prostaglandins inflammatory mediator that cyclooxygenase mediates can be suppressed; it it is maximally effective cyclooxygenase-2 inhibitors; having powerful anti-inflammatory analgesic action, its action intensity is 10 times of other NSAID (non-steroidal anti-inflammatory drug).
Published bromfenac sodium preparation method mainly includes the following two kinds: 1. with 2-amino-4-bromine benzophenone and 2-methylmercaptan ethyl acetoacetic ester for raw material, it is catalyst with aluminum chloride, carry out Friedel-crafts acidylate, reduce then through Raney's nickel or stannum, sodium hydroxide alkali hydrolysis salifying " one-step method " prepares bromfenac sodium; 2. with to bromobenzylcyanide and indoline for raw material; it is catalyst with boron chloride and aluminum chloride; carry out Friedel-crafts acidylate, become salt " one-step method " to prepare bromfenac sodium then through activated manganese dioxide oxidation, NBS or NCS halogenation, phosphoric acid hydrolysis, sodium hydroxide hydrolysis.
In the preparation process of bromfenac sodium; 7-(4-benzoyl bromide)-1; the hydrolysis step of 3-dihydro-indol-2-one easily generates bromfenac sodium dimer impurity; but the bromfenac sodium dimer impurity content generated is relatively low; and use prior art to be difficult to separate purification, its structural formula is:
Bromfenac sodium dimer impurity is not all sold on market at home and abroad, also without the preparation method that bibliographical information crosses bromfenac sodium dimer impurity, and need qualified bromfenac sodium dimer impurity as reference substance when carrying out quality analysis bromfenac sodium crude drug and preparation. Therefore, the preparation method research carrying out bromfenac sodium dimer impurity has great importance.
Summary of the invention
The preparation method that it is an object of the invention to provide a kind of bromfenac sodium dimer impurity, can prepare highly purified bromfenac sodium dimer impurity by this preparation method.
Blank for prior art, the preparation method of bromfenac sodium dimer impurity has been carried out a large amount of exploration by the present inventor, it have been unexpectedly found that: by 7-(4-benzoyl bromide)-1, the hydrolysis of 3-dihydro-indol-2-one generates bromfenac, bromfenac is carried out in the aqueous slkali of high concentration gradient increased temperature reaction, it is possible to promote the generation of bromfenac sodium dimer impurity; Make full use of bromfenac sodium dimer impurity and the nature difference of other compositions in reaction system, filter out suitable making beating and crystallization solvent, and suitable reaction condition is set, thus achieving the separation purification of bromfenac sodium dimer impurity simply, efficiently, prepare highly purified bromfenac sodium dimer impurity.
The object of the present invention is achieved like this:
The preparation method of the bromfenac sodium dimer impurity of the present invention, comprises the steps:
A), 7-(4-benzoyl bromide)-1,3-dihydro-indol-2-one is hydrolyzed in alkali hydroxide soln, after dichloromethane extraction, adds acetic acid neutralize, obtain bromfenac;
B), described bromfenac is added in the alkali hydroxide soln of 40%-80% weight/mass percentage composition, after reacting 1-3h in 70-80 DEG C, being further continued for being warming up to back flow reaction 2-4h, reaction cools down after terminating, add acetic acid and adjust pH to 5-8, crystallize, filters, and filter cake adopts ethyl acetate to pull an oar after washing, filter, collect filtrate, concentrating under reduced pressure, add acetone or acetonitrile crystallize obtains bromfenac sodium dimer impurity crude product;
C), described bromfenac sodium dimer impurity crude product is added in ethyl acetate, heating is to refluxing, add halogen acids and adjust pH to 1-2, cool down after reaction, filtering, the Organic Alcohol solution adding alkali metal hydroxide in filtrate adjusts pH to 8-10, adds Organic Alcohol crystallize, filter, obtain highly purified bromfenac sodium dimer impurity.
Further, the preparation method of the bromfenac sodium dimer impurity of the present invention, comprise the steps:
A), by 1.80kg7-(4-benzoyl bromide)-1,3-dihydro-indol-2-one is hydrolyzed in the alkali hydroxide soln of 15-25L15-25% weight/mass percentage composition, heating reflux reaction 1-3h, it is cooled to 20-25 DEG C, add dichloromethane extraction, pH to 7.0 adjusted by water layer acetic acid, filters, and 50 DEG C dry to obtain bromfenac;
B), 100g bromfenac is added in the alkali hydroxide soln of 350-450mL40%-80% weight/mass percentage composition, after reacting 1-3h in 70-80 DEG C, being further continued for being warming up to back flow reaction 2-4h, reaction cools down after terminating, add acetic acid and adjust pH to 5-8, crystallize, filters, and filter cake adopts 150-250mL ethyl acetate to pull an oar after washing, filter, collect filtrate, concentrating under reduced pressure, add acetone or acetonitrile crystallize obtains bromfenac sodium dimer impurity crude product;
C), 10g bromfenac sodium dimer impurity crude product is added in 50-70mL ethyl acetate, heating is to refluxing, add halogen acids and adjust pH to 1-2, slowly precipitate out solid, be cooled to 30-40 DEG C, filter, the Organic Alcohol solution adding alkali metal hydroxide in filtrate adjusts pH to 8-10, add Organic Alcohol crystallize, filter, obtain highly purified bromfenac sodium dimer impurity.
In the preparation method of the bromfenac sodium dimer impurity of the present invention, in step B) in, described bromfenac is added in the alkali hydroxide soln of 50%-60% weight/mass percentage composition, after reacting 1-3h in 70-80 DEG C, then be warming up to back flow reaction 2-4h.
In the preparation method of the bromfenac sodium dimer impurity of the present invention, described halogen acids is selected from hydrochloric acid or hydrobromic acid; Described Organic Alcohol is selected from methanol, ethanol or isopropanol; Described alkali metal hydroxide is selected from sodium hydroxide or potassium hydroxide.
In the preparation method of the bromfenac sodium dimer impurity of the present invention, at described step A) in, the weight/mass percentage composition of alkali hydroxide soln is 15%-25%; In stepb, add acetic acid and adjust pH to 6-7; In step C, it is cooled to 20-50 DEG C.
Inventor studies discovery by experiment: amide is easily hydrolyzed to carboxyl and amino in dilute alkaline soln, and bromfenac is easily obtained by reacting lactams by carboxyl and amino in the aqueous slkali that concentration is higher. Containing carboxyl and amino in the structure of bromfenac, the aqueous slkali that concentration is higher is heated and easily loses two molecular waters generation lactam structure compounds, when raising temperature further, can sloughing a part water further thus obtaining bromfenac sodium dimer impurity, its possible constructive ways is:
The present invention is by controlling 7-(4-benzoyl bromide)-1; the hydrolysising condition of 3-dihydro-indol-2-one; avoid one one-step hydrolysis and become salt; but first in dilute alkaline soln, hydrolysis generates bromfenac; bromfenac is carried out in the aqueous slkali of high concentration gradient increased temperature reaction again (after 70-80 DEG C of reaction 1-3h; it is warming up to back flow reaction 2-4h again), it is possible to promote the generation of bromfenac sodium dimer impurity, bromfenac sodium dimer impurity content >=70% in product. Bromfenac only in 70-80 DEG C of reaction, then mainly carries out acylation reaction in the aqueous slkali of high concentration, and corresponding product is mainly two lactam product, and the content of bromfenac sodium dimer impurity is lower than 30%; And directly bromfenac is heated to back flow reaction in the aqueous slkali of high concentration, then acylation reaction and the competition of ketone ketone condensation reaction reach balance, and the content generating two lactam product and bromfenac sodium dimer impurity respectively accounts for about 50%.
Inventor studies discovery by experiment: bromfenac sodium dimer impurity is dissolved in ethyl acetate, and bromfenac is only very slightly soluble in ethyl acetate, therefore after the present invention filter cake washing to collecting after crystallize, adopt ethyl acetate making beating can remove part bromfenac, the bromfenac sodium dimer impurity crude product of purity >=70% can be obtained then through concentrating under reduced pressure and anti-solvent crystallize.
In order to prepare highly purified bromfenac sodium dimer impurity, inventor adopts the process for purification such as the making beating of the recrystallization of prior art, organic solvent, column chromatography, one-tenth salt crystallize that bromfenac sodium dimer impurity crude product is refined, but is all difficult to the purity by bromfenac sodium dimer impurity and brings up to more than 90%. Inventor pass through great many of experiments and technological break-through, look for another way by the impurity generation chemical reaction in bromfenac sodium dimer impurity crude product, against expectation achieve the polishing purification of bromfenac sodium dimer impurity, purity brings up to more than 99%.
The impurity being primarily present in bromfenac sodium dimer impurity crude product is the bromfenac being slightly soluble in ethyl acetate; and bromfenac heat in acid condition can generation step A) back reaction cyclization obtain 7-(4-benzoyl bromide)-1,3-dihydro-indol-2-one. 7-(4-benzoyl bromide)-1,3-dihydro-indol-2-one has lactam structure, in alkalescence, it is possible to become to salt out with halogen acids; Though and bromfenac sodium dimer impurity there is also basic group amino, but inventor studies discovery by experiment, and it is difficult to become with halogen acids salt, therefore remains dissolved in solution, will not precipitate out, it may be possible to due to sterically hindered very big.By filtering to isolate 7-(4-benzoyl bromide)-1; after the halogen acid salt of 3-dihydro-indol-2-one; after filtrate furnishing alkalescence; add poor solvent Organic Alcohol; add the polarity of good solvent ethyl acetate; according to the principle of " similar mix ", the weak bromfenac sodium dimer impurity of polarity precipitates out in the Organic Alcohol and ethyl acetate mixed solvent of reversed polarity, and namely filtration obtains highly purified bromfenac sodium dimer impurity.
Compared with prior art, the invention has the beneficial effects as follows:
(1), generate bromfenac by the hydrolysis of 7-(4-benzoyl bromide)-1,3-dihydro-indol-2-one, bromfenac is carried out in the aqueous slkali of high concentration gradient increased temperature reaction, has promoted the generation of bromfenac sodium dimer impurity;
(2), to the filter cake collected after crystallize adopt ethyl acetate making beating can remove part bromfenac, the bromfenac sodium dimer impurity crude product of purity >=70% can be obtained then through concentrating under reduced pressure and anti-solvent crystallize;
(3), becoming to salt out by the impurity generation chemical reaction in bromfenac sodium dimer impurity crude product, achieve the polishing purification of bromfenac sodium dimer impurity simply, efficiently, purity brings up to more than 99%;
(4), preparation method provided by the invention easy, environmental benefit is good, and the target product purity of preparation is high, and yield is high.
Accompanying drawing explanation
The HPLC having related substance that Fig. 1 is the bromfenac sodium dimer impurity crude product of embodiment 2 preparation schemes.
The HPLC having related substance that Fig. 2 is the bromfenac sodium dimer impurity highly finished product of embodiment 5 preparation schemes.
Fig. 3 is the positive ion mode mass spectrum of the bromfenac sodium dimer impurity highly finished product of embodiment 5 preparation.
Fig. 4 is the negative ion mode mass spectrum of the bromfenac sodium dimer impurity highly finished product of embodiment 5 preparation.
Detailed description of the invention
In conjunction with accompanying drawing, the present invention is described below by way of specific embodiment. It will be appreciated by those skilled in the art that these embodiments are merely to illustrate the present invention, its scope not limited the present invention in any way.
Experimental technique in following embodiment, if no special instructions, is conventional method. Test material used in following embodiment, if no special instructions, is conventional commercial and obtains.
The preparation of embodiment 1 bromfenac
In 50L reactor; add 1.80kg7-(4-benzoyl bromide)-1,3-dihydro-indol-2-one, add the sodium hydrate aqueous solution of 20L20% weight/mass percentage composition; heating reflux reaction 2-h; cooling, adds dichloromethane extraction, and pH to 7.0 adjusted by water layer acetic acid; filter; 50 DEG C dry to obtain 1.46kg bromfenac, and the purity of bromfenac is 82.99%, and the content of bromfenac sodium dimer impurity is 13.3%.
The preparation of embodiment 2 bromfenac sodium dimer impurity crude product
Take the bromfenac of 100g embodiment 1 preparation, add in the sodium hydrate aqueous solution of 400mL50% weight/mass percentage composition, it is warming up to 75 DEG C of reaction 2h, it is further continued for being warming up to back flow reaction 3h, it is down to room temperature, add acetic acid and adjust pH to 6.5, crystallize, filter, filter cake is with after 100mL water washing, join making beating 1h in 200mL ethyl acetate, filter, collect filtrate, 50 DEG C of concentrating under reduced pressure, add acetonitrile stirring and crystallizing, filter, 50 DEG C dry to obtain 40.2g bromfenac sodium dimer impurity crude product, the purity of bromfenac sodium dimer impurity is 77.05%, the HPLC having related substance schemes as shown in Figure 1.
The preparation of embodiment 3 bromfenac sodium dimer impurity crude product
Take the bromfenac of 100g embodiment 1 preparation, add in the sodium hydrate aqueous solution of 350mL45% weight/mass percentage composition, it is warming up to 70 DEG C of reaction 3h, it is further continued for being warming up to back flow reaction 4h, it is down to room temperature, adds acetic acid and adjust pH to 5.5, crystallize, filter, filter cake is with, after 100mL water washing, joining making beating 1h in 150mL ethyl acetate, filter, collect filtrate, 50 DEG C of concentrating under reduced pressure, add acetonitrile stirring and crystallizing, filter, 50 DEG C dry to obtain 39.6g bromfenac sodium dimer impurity crude product, and the purity of bromfenac sodium dimer impurity is 75.81%.
The preparation of embodiment 4 bromfenac sodium dimer impurity crude product
Take the bromfenac of 100g embodiment 1 preparation, add in the sodium hydrate aqueous solution of 450mL75% weight/mass percentage composition, it is warming up to 80 DEG C of reaction 1h, it is further continued for being warming up to back flow reaction 2h, it is down to room temperature, adds acetic acid and adjust pH to 7.5, crystallize, filter, filter cake is with, after 100mL water washing, joining making beating 1h in 250mL ethyl acetate, filter, collect filtrate, 50 DEG C of concentrating under reduced pressure, add acetonitrile stirring and crystallizing, filter, 50 DEG C dry to obtain 39.1g bromfenac sodium dimer impurity crude product, and the purity of bromfenac sodium dimer impurity is 75.45%.
The preparation of comparative example 1 bromfenac sodium dimer impurity crude product
Take the bromfenac of 100g embodiment 1 preparation, add in the sodium hydrate aqueous solution of 400mL50% weight/mass percentage composition, be warming up to 75 DEG C of reaction 5-h, it is down to room temperature, adds acetic acid and adjust pH to 6.5, crystallize, filtering, filter cake is with, after 100mL water washing, joining making beating 1-h in 200mL ethyl acetate, filter, collect filtrate, 50 DEG C of concentrating under reduced pressure, add acetonitrile stirring and crystallizing, filtering, 50 DEG C dry to obtain 41.4g bromfenac sodium dimer impurity crude product, and the purity of bromfenac sodium dimer impurity is 26.72%.
The preparation of comparative example 2 bromfenac sodium dimer impurity crude product
Take the bromfenac of 100g embodiment 1 preparation, add in the sodium hydrate aqueous solution of 400mL50% weight/mass percentage composition, be warming up to back flow reaction 5-h, it is down to room temperature, adds acetic acid and adjust pH to 6.5, crystallize, filtering, filter cake is with, after 100mL water washing, joining making beating 1-h in 200mL ethyl acetate, filter, collect filtrate, 50 DEG C of concentrating under reduced pressure, add acetonitrile stirring and crystallizing, filtering, 50 DEG C dry to obtain 40.8g bromfenac sodium dimer impurity crude product, and the purity of bromfenac sodium dimer impurity is 48.94%.
The preparation of embodiment 5 bromfenac sodium dimer impurity highly finished product
The bromfenac sodium dimer impurity crude product 10g of Example 2 preparation, add 60mL ethyl acetate, it is warming up to backflow, add hydrochloric acid and adjust pH to 1��2, slowly precipitate out solid, it is cooled to 40 DEG C, collect by filtration filtrate, add sodium hydrate methanol solution and adjust pH to 8, add 10mL methanol stirring and crystallizing, filter, dry to obtain 4.5g bromfenac sodium dimer impurity highly finished product, the purity of bromfenac sodium dimer impurity is 99.68%, the HPLC having related substance schemes as shown in Figure 2, mass spectrum is Fig. 3 such as, (cation molecular ion peak M+1=615.1 shown in Fig. 4, anionic molecule quasi-molecular ions M-1=613.0, then molecular weight M=614.1).
The preparation of embodiment 6 bromfenac sodium dimer impurity highly finished product
The bromfenac sodium dimer impurity crude product 10g of Example 2 preparation, add 60mL ethyl acetate, be warming up to backflow, add hydrochloric acid and adjust pH to 1��2, slowly precipitate out solid, it is cooled to 30 DEG C, collects by filtration filtrate, add sodium hydroxide alcoholic solution and adjust pH to 10, add 15mL ethanol stirring and crystallizing, filtering, dry to obtain 4.1g bromfenac sodium dimer impurity highly finished product, the purity of bromfenac sodium dimer impurity is 99.70%.
The preparation of embodiment 7 bromfenac sodium dimer impurity highly finished product
The bromfenac sodium dimer impurity crude product 10g of Example 2 preparation, add 60mL ethyl acetate, be warming up to backflow, add hydrobromic acid and adjust pH to 1��2, slowly precipitate out solid, it is cooled to 30 DEG C, collects by filtration filtrate, add sodium hydroxide aqueous isopropanol and adjust pH to 10, add 15mL isopropanol stirring and crystallizing, filtering, dry to obtain 4.4g bromfenac sodium dimer impurity highly finished product, the purity of bromfenac sodium dimer impurity is 99.61%.
Above content is in conjunction with concrete preferred implementation further description made for the present invention, it is impossible to assert that specific embodiment of the invention is confined to these explanations. For general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, it is also possible to make some simple deduction or replace, protection scope of the present invention all should be considered as belonging to.
Claims (9)
1. the preparation method of a bromfenac sodium dimer impurity, it is characterised in that: comprise the steps:
A), 7-(4-benzoyl bromide)-1,3-dihydro-indol-2-one is hydrolyzed in alkali hydroxide soln, after dichloromethane extraction, adds acetic acid neutralize, obtain bromfenac;
B), described bromfenac is added in the alkali hydroxide soln of 40%-80% weight/mass percentage composition, after reacting 1-3h in 70-80 DEG C, being further continued for being warming up to back flow reaction 2-4h, reaction cools down after terminating, add acetic acid and adjust pH to 5-8, crystallize, filters, and filter cake adopts ethyl acetate to pull an oar after washing, filter, collect filtrate, concentrating under reduced pressure, add acetone or acetonitrile crystallize obtains bromfenac sodium dimer impurity crude product;
C), described bromfenac sodium dimer impurity crude product is added in ethyl acetate, heating is to refluxing, add halogen acids and adjust pH to 1-2, cool down after reaction, filtering, the Organic Alcohol solution adding alkali metal hydroxide in filtrate adjusts pH to 8-10, adds Organic Alcohol crystallize, filter, obtain bromfenac sodium dimer impurity;
The molecular formula of described bromfenac sodium dimer impurity is:
2. the preparation method of bromfenac sodium dimer impurity according to claim 1, it is characterised in that: comprise the steps:
A), by 1.80kg7-(4-benzoyl bromide)-1,3-dihydro-indol-2-one is hydrolyzed in the alkali hydroxide soln of 15-25L15-25% weight/mass percentage composition, heating reflux reaction 1-3h, cooling, add dichloromethane extraction, pH to 7.0 adjusted by water layer acetic acid, filters, and 50 DEG C dry to obtain bromfenac;
B), 100g bromfenac is added in the alkali hydroxide soln of 350-450mL40%-80% weight/mass percentage composition, after reacting 1-3h in 70-80 DEG C, being further continued for being warming up to back flow reaction 2-4h, reaction cools down after terminating, add acetic acid and adjust pH to 5-8, crystallize, filters, and filter cake adopts 150-250mL ethyl acetate to pull an oar after washing, filter, collect filtrate, concentrating under reduced pressure, add acetone or acetonitrile crystallize obtains bromfenac sodium dimer impurity crude product;
C), 10g bromfenac sodium dimer impurity crude product is added in 50-70mL ethyl acetate, heating is to refluxing, add halogen acids and adjust pH to 1-2, slowly precipitate out solid, be cooled to 30-40 DEG C, filter, the Organic Alcohol solution adding alkali metal hydroxide in filtrate adjusts pH to 8-10, add Organic Alcohol crystallize, filter, obtain bromfenac sodium dimer impurity.
3. the preparation method of bromfenac sodium dimer impurity according to claim 1 or claim 2, it is characterized in that: in stepb, described bromfenac is added in the alkali hydroxide soln of 50%-60% weight/mass percentage composition, after reacting 1-3h in 70-80 DEG C, then be warming up to back flow reaction 2-4h.
4. the preparation method of bromfenac sodium dimer impurity according to claim 1 or claim 2, it is characterised in that: described halogen acids is selected from hydrochloric acid or hydrobromic acid.
5. the preparation method of bromfenac sodium dimer impurity according to claim 1 or claim 2, it is characterised in that: described Organic Alcohol is selected from methanol, ethanol or isopropanol.
6. the preparation method of bromfenac sodium dimer impurity according to any one of claim 1 to 2, it is characterised in that: in described step A), the weight/mass percentage composition of alkali hydroxide soln is 15%-25%.
7. the preparation method of bromfenac sodium dimer impurity according to any one of claim 1 to 2, it is characterised in that: described alkali metal hydroxide is selected from sodium hydroxide or potassium hydroxide.
8. the preparation method of bromfenac sodium dimer impurity according to claim 1 or claim 2, it is characterised in that: in stepb, add acetic acid and adjust pH to 6-7.
9. the preparation method of bromfenac sodium dimer impurity according to claim 1, it is characterised in that: in step C, it is cooled to 20-50 DEG C.
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Inventor after: Deng Jun Inventor after: Tan Zhenyou Inventor after: Ye Qiongxian Inventor after: Du Jing Inventor before: Deng Jun Inventor before: Tan Zhenyou Inventor before: Jin Lianming Inventor before: Huang Aijun Inventor before: Shao Guangzhi Inventor before: Ye Qiongxian Inventor before: Du Jing |
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